Lamotrigine (Page 15 of 19)

Phenobarbital, Primidone

The addition of phenobarbital or primidone decreases lamotrigine steady-state concentrations by approximately 40%.


Lamotrigine has no appreciable effect on steady-state phenytoin plasma concentrations in patients with epilepsy. The addition of phenytoin decreases lamotrigine steady-state concentrations by approximately 40%.


Steady-state trough plasma concentrations of lamotrigine were not affected by concomitant pregabalin (200 mg 3 times daily) administration. There are no pharmacokinetic interactions between lamotrigine and pregabalin.


In ten male volunteers, rifampin (600 mg/day for 5 days) significantly increased the apparent clearance of a single 25 mg dose of lamotrigine by approximately 2-fold (AUC decreased by approximately 40%).


In a 14 healthy volunteers study, multiple oral doses of lamotrigine 400 mg daily had no clinically significant effect on the single-dose pharmacokinetics of risperidone 2 mg and its active metabolite 9-OH risperidone. Following the coadministration of risperidone 2 mg with lamotrigine, 12 of the 14 volunteers reported somnolence compared with 1 out of 20 when risperidone was given alone, and none when lamotrigine was administered alone.


Topiramate resulted in no change in plasma concentrations of lamotrigine. Administration of lamotrigine resulted in a 15% increase in topiramate concentrations.


When lamotrigine was administered to healthy volunteers (n = 18) receiving valproate, the trough steady-state valproate plasma concentrations decreased by an average of 25% over a 3-week period, and then stabilized. However, adding lamotrigine to the existing therapy did not cause a change in valproate plasma concentrations in either adult or pediatric patients in controlled clinical trials.

The addition of valproate increased lamotrigine steady-state concentrations in normal volunteers by slightly more than 2-fold. In one trial, maximal inhibition of lamotrigine clearance was reached at valproate doses between 250 and 500 mg/day and did not increase as the valproate dose was further increased.


In a study in 18 patients with epilepsy, coadministration of zonisamide (200 to 400 mg/day) with lamotrigine (150 to 500 mg/day for 35 days) had no significant effect on the pharmacokinetics of lamotrigine.

Known Inducers or Inhibitors of Glucuronidation

Drugs other than those listed above have not been systematically evaluated in combination with lamotrigine. Since lamotrigine is metabolized predominately by glucuronic acid conjugation, drugs that are known to induce or inhibit glucuronidation may affect the apparent clearance of lamotrigine and doses of lamotrigine may require adjustment based on clinical response.


In vitro assessment of the inhibitory effect of lamotrigine at OCT2 demonstrate that lamotrigine, but not the N(2)-glucuronide metabolite, is an inhibitor of OCT2 at potentially clinically relevant concentrations, with IC 50 value of 53.8 μM [see Drug Interactions (7)] .

Results of in vitro experiments suggest that clearance of lamotrigine is unlikely to be reduced by concomitant administration of amitriptyline, clonazepam, clozapine, fluoxetine, haloperidol, lorazepam, phenelzine, sertraline, or trazodone.

Results of in vitro experiments suggest that lamotrigine does not reduce the clearance of drugs eliminated predominantly by CYP2D6.

Specific Populations

Renal Impairment

Twelve volunteers with chronic renal failure (mean creatinine clearance: 13 mL/min, range: 6 to 23) and another six individuals undergoing hemodialysis were each given a single 100 mg dose of lamotrigine. The mean plasma half-lives determined in the study were 42.9 hours (chronic renal failure), 13 hours (during hemodialysis), and 57.4 hours (between hemodialysis) compared with 26.2 hours in healthy volunteers. On average, approximately 20% (range: 5.6 to 35.1) of the amount of lamotrigine present in the body was eliminated by hemodialysis during a 4-hour session [see Dosage and Administration (2.1)].

Hepatic Disease

The pharmacokinetics of lamotrigine following a single 100 mg dose of lamotrigine were evaluated in 24 subjects with mild, moderate, and severe hepatic impairment (Child-Pugh classification system) and compared with 12 subjects without hepatic impairment. The subjects with severe hepatic impairment were without ascites (n = 2) or with ascites (n = 5). The mean apparent clearances of lamotrigine in subjects with mild (n = 12), moderate (n = 5), severe without ascites (n = 2), and severe with ascites (n = 5) liver impairment were 0.30 ± 0.09, 0.24 ± 0.1, 0.21 ± 0.04, and 0.15 ± 0.09 mL/min/kg, respectively, as compared with 0.37 ± 0.1 mL/min/kg in the healthy controls. Mean half-lives of lamotrigine in subjects with mild, moderate, severe without ascites, and severe with ascites hepatic impairment were 46 ± 20, 72 ± 44, 67 ± 11, and 100 ± 48 hours, respectively, as compared with 33 ± 7 hours in healthy controls [see Dosage and Administration (2.1)].


Pediatric Subjects

The pharmacokinetics of lamotrigine following a single 2 mg/kg dose were evaluated in two studies in pediatric subjects (n = 29 for subjects aged 10 months to 5.9 years and n = 26 for subjects aged 5 to 11 years). Forty-three subjects received concomitant therapy with other AEDs and 12 subjects received lamotrigine as monotherapy. Lamotrigine pharmacokinetic parameters for pediatric patients are summarized in Table 16.

Population pharmacokinetic analyses involving subjects aged 2 to 18 years demonstrated that lamotrigine clearance was influenced predominantly by total body weight and concurrent AED therapy. The oral clearance of lamotrigine was higher, on a body weight basis, in pediatric patients than in adults. Weight-normalized lamotrigine clearance was higher in those subjects weighing less than 30 kg compared with those weighing greater than 30 kg. Accordingly, patients weighing less than 30 kg may need an increase of as much as 50% in maintenance doses, based on clinical response, as compared with subjects weighing more than 30 kg being administered the same AEDs [see Dosage and Administration (2.2)]. These analyses also revealed that, after accounting for body weight, lamotrigine clearance was not significantly influenced by age. Thus, the same weight-adjusted doses should be administered to children irrespective of differences in age. Concomitant AEDs which influence lamotrigine clearance in adults were found to have similar effects in children.

Table 16. Mean Pharmacokinetic Parameters in Pediatric Subjects with Epilepsy
Carbamazepine, phenytoin, phenobarbital, and primidone have been shown to increase the apparent clearance of lamotrigine. Estrogen-containing oral contraceptives, rifampin, and the protease inhibitors lopinavir/ritonavir and atazanavir/ritonavir have also been shown to increase the apparent clearance of lamotrigine [see Drug Interactions (7)].
Two subjects were included in the calculation for mean T max.
Parameter not estimated.

Pediatric Study Population

Number of Subjects

T max (h)

t 1/2 (h)

CL/F (mL/min/kg)

Ages 10 months to 5.3 years

Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone *



(1 to 5.9)


(5.7 to 11.4)


(2.44 to 5.28)

Subjects taking antiepileptic drugs with no known effect on the apparent clearance of lamotrigine



(2.9 to 6.1)


(12.9 to 27.1)


(0.75 to 2.42)

Subjects taking valproate only



(1 to 6)


(29.5 to 52.5)


(0.23 to 0.77)

Ages 5 to 11 years

Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone *



(1 to 3)


(3.8 to 9.8)


(1.35 to 5.58)

Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone * plus valproate



(1 to 6.4)


(7 to 31.2)


(0.39 to 1.93)

Subjects taking valproate only



(3 to 6)


(50.7 to 73.7)


(0.21 to 0.26)

Ages 13 to 18 years

Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone *



Subjects taking carbamazepine, phenytoin, phenobarbital, or primidone * plus valproate



Subjects taking valproate only



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